DESCRIPTION: A recent epidemic of optic nerve blindness affecting 50,000 people in Cuba was successfully treated through vitamin therapy. The clinical features of the Cuban epidemic of optic neuropathy (CEON) were similar to both tobacco-alcohol-amblyopia and Leber's hereditary optic neuropathy (Leber's). In each case, there is evidence that singular or combined insults to mitochondrial oxidative phosphorylation impair ATP production, however, this does not explain why other metabolically active tissues such as liver or heart are spared. Therefore, the questions remain: why nerves, why the optic nerve, why the papillo macular bundle? The PI hypothesizes that a common pathophysiological mechanism involving impaired mitochondria and the ATP expensive mitochondrial axonal transportation underlies genetic optic nerve diseases such as Leber s metabolic and nutritional diseases such as CEON, and a variety of toxic optic neuropathies as well. Total ATP depletion due to blockage of mitochondrial transportation may trigger cell death although conventional wisdom suggests that partial optic nerve axonal stasis (e.g. papilledema) does not usually lead to degeneration. The PI is studying the association between the compromise of mitochondrial function and optic neuropathies and investigating causality and mechanism. Four trips to Cuba have given the investigator unparalleled access to examine patients and obtain tissues (150 sera and CSF samples, sural nerve biopsies, and an eye with optic nerve all secured at the height of the epidemic) from CEON patients. The pathophysiology of CEON, as revealed by clinical, pathological, and blood biochemical correlations suggests that deranged oxidative phosphorylation may be the source of this disease. He has succeeded in developing an analogous animal model of deranged oxidative phosphorylation by administering chronic, low doses of methanol to folic acid deficient rats. With parallels to CEON, the animal model has elevated serum formate levels and optic nerve axonal vacuolation, reflecting blocked transport, found only at the lamina cribrosa. The PI is continuing to refine and characterize this model by following the time course of injury. The animal model will permit us to examine the relationship between elevated formate, the inhibition of oxidative phosphorylation as measured by ATP level, mitochondrial transport, and neuronal injury (assessed via morphological, ultrastructural, and biochemical analysis). These findings will permit to test the hypothesis that in susceptible neuronal tissues, mitochondrial derangement leads to ATP depletion, hence to decreased mitochondrial transportation which results in even further ATP depletion as part of a vicious cycle that collapses the system. By modulating and trying to prevent this vicious cycle, he will gain better understanding of the kinetics of the mitochondrial pathways. He expects this to lead to new treatments for a variety of genetic and acquired optic neuropathies.